Intravenous fosfomycin for the treatment of patients with bone and joint infections: a review.

INTRODUCTION: Fosfomycin is a wide spectrum bactericidal antibiotic with a unique mode of action, low toxicity, and good penetration in tissues with deep-seated infections, including bone and joint infections. AREAS COVERED: Data were extracted from 19 published articles. Three hundred and sixty-five patients, with broad age range, received intravenous fosfomycin for the treatment of bone and joint infections (including arthritis, acute and chronic osteomyelitis, discitis, periprosthetic joint infection). Fosfomycin was given as part of a combination antimicrobial therapy in the majority of patients (93.7%). The dosage of fosfomycin ranged from 4 g/day (in one case) to 24 g/day. The dosage of fosfomycin, in some cases, mostly pediatric, was calculated based on body weight, ranging from 50 mg/kg/day to 250 mg/kg/day. The duration of fosfomycin treatment ranged from a couple of days up to 3 months. The most common isolated pathogen was Staphylococcus aureus (38.9%). Three hundred patients (82.2%) were successfully treated. Fosfomycin was well tolerated, as few patients developed mild adverse events, mostly gastrointestinal discomfort, hypernatremia, skin rash, and neutropenia. EXPERT OPINION: The available data suggests that intravenous fosfomycin may be beneficial for the treatment of patients with bone and joint infections, especially when used as part of a combination antibiotic regimen.

Clinical use of intravenous polymyxin B for the treatment of patients with multidrug-resistant Gram-negative bacterial infections: An evaluation of the current evidence.

OBJECTIVES: The epidemic dimensions of the emergence of multidrug-resistant (MDR) Gram-negative bacterial infections have led to the revival of old antibiotics, including the polymyxins. METHODS: We performed a review and meta-analysis to evaluate the current literature data regarding the effectiveness and safety of intravenous polymyxin B in patients with MDR Gram-negative bacterial infections and the overall mortality and nephrotoxicity in patients treated with intravenous polymyxin B either as monotherapy or combination therapy. RESULTS: A total of 5 prospective and 28 retrospective studies, 1 cross-sectional study, 2 retrospective case series and 7 case reports provided data regarding the effectiveness and/or toxicity of intravenous polymyxin B. All-cause mortality of 2910 patients (from 27 studies) who received intravenous polymyxin B was 41.2% (95% CI 35.5-47.0%). All-cause nephrotoxicity of 2994 patients (from 28 studies) treated with intravenous polymyxin B was 40.7% (95% CI 35.0-46.6%). Renal failure among 2111 patients (from 14 studies) was 11.2% (95% CI 8.7-13.9%). CONCLUSION: Mortality of patients treated with intravenous polymyxin B is similar to the literature-reported mortality of patients treated with intravenous colistin, while nephrotoxicity associated with polymyxin B use is possibly milder compared with colistin use based on literature data. Head-to-head prospective studies would help to clarify the benefit of polymyxin B over colistin. However, a critical evaluation of the existing worldwide literature data supports the need for availability of the intravenous formulation of polymyxin B as a potentially useful option for the treatment of patients with MDR and extensively drug-resistant (XDR) Gram-negative bacterial infections.

Intravenous fosfomycin for the treatment of patients with central nervous system infections: evaluation of the published evidence.

INTRODUCTION: Central nervous system (CNS) infections have considerable morbidity and mortality. Fosfomycin is a broad spectrum bactericidal antibiotic with favorable pharmacokinetic properties and low toxicity, satisfactory penetration in the cerebrospinal fluid and is authorized for the treatment of bacterial meningitis. AREAS COVERED: The objective of this analysis was to evaluate the available data regarding the effectiveness and safety of intravenous fosfomycin for the treatment of CNS infections. Thirty-two relevant publications were identified. Data from 224 patients who received intravenous fosfomycin as treatment for CNS infections were evaluated. Overall, 93.8% of patients were cured from the infection. Staphylococcus was the most frequent pathogen; Streptococcus pneumoniae, Neisseria meningitidis, and several other microbial agents, including multi-drug resistant and extensively drug-resistant bacteria, were also implicated. Fosfomycin was given as part of a combination treatment in the vast majority of the patients. The dosage of fosfomycin ranged between 4 g and 24 g per day; a regimen with 14-16 g per day was used in the majority of the cases. Fosfomycin was generally well tolerated. EXPERT OPINION: The evaluation of the published evidence suggests that fosfomycin may be beneficial in the treatment of patients with CNS infections.

Developments on antibiotics for multidrug resistant bacterial Gram-negative infections.

Introduction: The constantly increasing spread of severe infections due to multidrug-resistant (MDR) Gram-negative bacteria (GNB) is a critical threat to the global medical community. After a long period of antibiotic pipeline pause, new antibiotic compounds are commercially available or are at late stages of clinical evaluation, promising to augment the therapeutic armamentarium of clinicians against deadly pathogens. Areas covered: This review summarizes available data regarding agents with potent activity against critical MDR Gram-negative pathogens, which urgently require new efficient antibiotics. Recently approved antibiotic formulations; and agents in advanced stages of development, including combinations of ß-lactam/ß-lactamase inhibitor, novel cephalosporins (cefiderocol), tetracyclines (eravacycline), aminoglycosides (plazomicin), quinolones (delafloxacin and finafloxacin) and pleuromutilins (lefamulin) are discussed in this review. Expert opinion: The recent introduction of new antibiotics into clinical practice is an encouraging step after a long period of pipeline stagnation. New formulations will be a useful option for clinicians to treat serious infections caused by several MDR Gram-negative pathogens. However, most of the new compounds are based on modifications of traditional antibiotic structures challenging their longevity as therapeutic options. More investment is needed for the discovery and clinical development of truly innovative and effective antibiotics without cross-resistance to currently used antibiotics.

Synergistic activity of colistin with azidothymidine against colistin-resistant Klebsiella pneumoniae clinical isolates collected from inpatients in Greek hospitals.

BACKGROUND: New antibiotics are urgently needed to treat multi-drug resistant infections; however, production of novel antibiotics is diminishing. Synergistic combination drug therapy to enhance the activity of available antibiotics may improve management of patients with resistant infections. METHODS: Colistin-resistant Klebsiella pneumoniae isolates were collected from inpatients in 10 Greek hospitals and used to study combination activity of colistin plus azidothymidine. Combination activity was evaluated with the sum of fractional inhibitory concentrations (ΣFIC) using the mini checkerboard broth microdilution method. RESULTS: A hundred individual strains were tested. Synergistic activity was noted in 79% (79/100) of isolates and additive activity in the remaining 21% (21/100). ΣFIC50 and ΣFIC90 were 0.28 and 0.56, respectively. CONCLUSION: Colistin with azidothymidine exhibited promising synergistic activity against colistin-resistant Klebsiella pneumoniae isolates warranting further investigation of the combination.

Resistance to fosfomycin: Mechanisms, Frequency and Clinical Consequences.

Fosfomycin has been used for the treatment of infections due to susceptible and multidrug-resistant (MDR) bacteria. It inhibits bacterial cell wall synthesis through a unique mechanism of action at a step prior to that inhibited by ß-lactams. Fosfomycin enters the bacterium through membrane channels/transporters and inhibits MurA, which initiates peptidoglycan (PG) biosynthesis of the bacterial cell wall. Several bacteria display inherent resistance to fosfomycin mainly through MurA mutations. Acquired resistance involves, in order of decreasing frequency, modifications of membrane transporters that prevent fosfomycin from entering the bacterial cell, acquisition of plasmid-encoded genes that inactivate fosfomycin, and MurA mutations. Fosfomycin resistance develops readily in vitro but less so in vivo. Mutation frequency is higher among Pseudomonas aeruginosa and Klebsiella spp. compared with Escherichia coli and is associated with fosfomycin concentration. Mutations in cAMP regulators, fosfomycin transporters and MurA seem to be associated with higher biological cost in Enterobacteriaceae but not in Pseudomonas spp. The contribution of fosfomycin inactivating enzymes in emergence and spread of fosfomycin resistance currently seems low-to-moderate, but their presence in transferable plasmids may potentially provide the best means for the spread of fosfomycin resistance in the future. Their co-existence with genes conferring resistance to other antibiotic classes may increase the emergence of MDR strains. Although susceptibility rates vary, rates seem to increase in settings with higher fosfomycin use and among multidrug-resistant pathogens.

Activity of TP-6076 against carbapenem-resistant Acinetobacter baumannii isolates collected from inpatients in Greek hospitals.

TP-6076 is a synthetic fluorocycline antibiotic that inhibits bacterial protein synthesis. In this study, carbapenem-resistant Acinetobacter baumannii clinical isolates from 13 Greek hospitals were tested for susceptibility to TP-6076 and comparator antibiotics. Broth microdilution plates were used to determine minimum inhibitory concentrations (MICs). A total of 121 non-duplicate A. baumannii isolates were tested. The MIC50 and MIC90 values of TP-6076 were 0.03 mg/L and 0.06 mg/L, respectively. Tigecycline was the second most active antibiotic (MIC90, 2 mg/L), followed by minocycline (MIC90, 8 mg/L). TP-6076 exhibited MIC90 values that were one dilution lower against tigecycline- and minocycline-susceptible isolates than against resistant isolates. There was no difference in the MIC90 value for colistin-susceptible or -resistant isolates. In conclusion, TP-6076 exhibited greater antimicrobial activity in vitro against carbapenem-resistant A. baumannii than comparator antibiotics.

Prolonged versus short-term intravenous infusion of antipseudomonal ß-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials.

BACKGROUND: The findings of randomised controlled trials (RCT), observational studies, and meta-analyses vary regarding the effectiveness of prolonged ß-lactam infusion. We aimed to identify the effectiveness of prolonged versus short-term infusion of antipseudomonal ß-lactams in patients with sepsis. METHODS: We did a systematic review and meta-analysis to compare prolonged versus short-term intravenous infusion of antipseudomonal ß-lactams in patients with sepsis. Two authors independently searched PubMed, Scopus, and the Cochrane Library of clinical trials until November, 2016, without date or language restrictions. Any RCT comparing mortality or clinical efficacy of prolonged (continuous or ≥3 h) versus short-term (≤60 min) infusion of antipseudomonal ß-lactams for the treatment of patients with sepsis was eligible. Studies were excluded if they were not RCTs, the antibiotics in the two arms were not the same, neither mortality nor clinical efficacy was reported, only pharmacokinetic or pharmacodynamic outcomes were reported, or if ten or fewer patients were enrolled or randomised. Data were extracted in prespecified forms and we then did a meta-analysis using a Mantel-Haenszel random-effects model. The primary outcome was all-cause mortality at any timepoint. This meta-analysis is registered with the PROSPERO database, number CRD42016051678, and is reported according to PRISMA guidelines. FINDINGS: 2196 articles were identified and screened, and 22 studies (1876 patients) were included in the meta-analysis. According to the Grading of Recommendations Assessment, Development, and Evaluation tool, the quality of evidence for mortality was high. Carbapenems, penicillins, and cephalosporins were studied. Patients with variable age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, severity of sepsis and renal function were enrolled. Prolonged infusion was associated with lower all-cause mortality than short-term infusion (risk ratio [RR] 0·70, 95% CI 0·56-0·87). Heterogeneity was not observed (p=0·93, I2=0%). The funnel plot and the Egger's test (p=0·44) showed no evidence of publication bias. INTERPRETATION: Prolonged infusion of antipseudomonal ß-lactams for the treatment of patients with sepsis was associated with significantly lower mortality than short-term infusion. Further studies in specific subgroups of patients according to age, sepsis severity, degree of renal dysfunction, and immunocompetence are warranted. FUNDING: None.

Inhaled colistin monotherapy for respiratory tract infections in adults without cystic fibrosis: a systematic review and meta-analysis.

BACKGROUND: Inhaled colistin is becoming increasingly popular against respiratory tract infections caused by multidrug resistant (MDR) Gram-negative bacteria because it may overcome the problems associated with intravenous (IV) administration. OBJECTIVE: To investigate the effectiveness and safety of inhaled colistin as monotherapy (without concomitant IV administration of colistin) in the treatment of respiratory tract infections caused by MDR or colistin-only susceptible Gram-negative bacteria. METHODS: PubMed and Scopus databases were searched. A systematic review and meta-analysis were conducted. RESULTS: Twelve studies (373 patients receiving inhaled colistin for respiratory tract infection) were included. Ten studies evaluated patients with pneumonia (including 8 studies with ventilator-associated pneumonia) and 2 studies evaluated patients with ventilator-associated tracheobronchitis. Patients with infections due to MDR Acinetobacter baumannii and Pseudomonas aeruginosa were mainly studied. Daily dose of inhaled colistin and treatment duration varied in the individual studies. The pooled all-cause mortality was 33.8% (95% CI 24.6% - 43.6%), clinical success was 70.4% (58.5% - 81.1%) and eradication of Gram-negative bacteria was shown in 71.3% (57.6% - 83.2%) of cases. CONCLUSIONS: Inhaled colistin monotherapy may deserve further consideration as a mode for colistin administration for the treatment of respiratory tract infections caused by MDR A. baumannii and P. aeruginosa.